bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2024–03–10
eightteen papers selected by
Oltea Sampetrean, Keio University
  1. Immunometabolic Maladaptations to the Tumor Microenvironment.
  2. Metabolic adaptations determine whether natural killer cells fail or thrive within the tumor microenvironment.
  3. A glutamine tug-of-war between cancer and immune cells: recent advances in unraveling the ongoing battle.
  4. Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth.
  5. Advances in metabolic reprogramming of NK cells in the tumor microenvironment on the impact of NK therapy.
  6. Overcoming the limitations of immunotherapy in pancreatic ductal adenocarcinoma: Combining radiotherapy and metabolic targeting therapy.
  7. Metabolic remodeling in cancer and senescence and its therapeutic implications.
  8. The effects of metabolism on the immune microenvironment in colorectal cancer.
  9. Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression.
  10. Lactic acid in macrophage polarization: A factor in carcinogenesis and a promising target for cancer therapy.
  11. CD8+ T cells sustain antitumor response by mediating crosstalk between adenosine A2A receptor and glutathione/GPX4.
  12. Dynamic interactions in the tumor niche: how the cross-talk between CAFs and the tumor microenvironment impacts resistance to therapy.
  13. Targeting tryptophan catabolism in ovarian cancer to attenuate macrophage infiltration and PD-L1 expression.
  14. Metabolomics analysis reveals novel serum metabolite alterations in cancer cachexia.
  15. Fatty acid oxidation fuels natural killer cell responses against infection and cancer.
  16. Severely polarized extracellular acidity around tumour cells.
  17. Histone lactylation bridges metabolic reprogramming and epigenetic rewiring in driving carcinogenesis: Oncometabolite fuels oncogenic transcription.
  18. Identification of the novel biomarkers involved in the mitochondrial metabolism-related reactive oxygen species and their role in lung cancer T-cell exhaustion and immunotherapy.
  1. Cold Spring Harb Perspect Med. 2024 Mar 04. pii: a041547. [Epub ahead of print]
    Immunometabolic Maladaptations to the Tumor Microenvironment.
    Emma S Hathaway, Erin Q Jennings, Jeffrey C Rathmell.
      Tumors consist of cancer cells and a wide range of tissue resident and infiltrating cell types. Tumor metabolism, however, has largely been studied on whole tumors or cancer cells and the metabolism of infiltrating immune cells remains poorly understood. It is now clear from a range of analyses and metabolite rescue studies that metabolic adaptations to the tumor microenvironment (TME) directly impede T-cell and macrophage effector functions. The drivers of metabolic adaptation to the TME and metabolic immune suppression include depletion of essential nutrients, accumulation of waste products or immune suppression metabolites, and metabolic signaling through altered posttranslational modifications. Each infiltrating immune cell subset differs, however, with specific metabolic requirements and adaptations that can be maladaptive for antitumor immunity. Here, we review T-cell and macrophage adaptation and metabolic immune suppression in solid tumors. Ultimately, understanding and addressing these challenges will improve cancer immunotherapy and adoptive chimeric antigen receptor T-cell therapies.
    DOI:  https://doi.org/10.1101/cshperspect.a041547
  2. Immunol Rev. 2024 Mar 09.
    Metabolic adaptations determine whether natural killer cells fail or thrive within the tumor microenvironment.
    Adnan Moinuddin, Sophie M Poznanski, Ana L Portillo, Jonathan K Monteiro, Ali A Ashkar.
      Natural Killer (NK) cells are a top contender in the development of adoptive cell therapies for cancer due to their diverse antitumor functions and ability to restrict their activation against nonmalignant cells. Despite their success in hematologic malignancies, NK cell-based therapies have been limited in the context of solid tumors. Tumor cells undergo various metabolic adaptations to sustain the immense energy demands that are needed to support their rapid and uncontrolled proliferation. As a result, the tumor microenvironment (TME) is depleted of nutrients needed to fuel immune cell activity and contains several immunosuppressive metabolites that hinder NK cell antitumor functions. Further, we now know that NK cell metabolic status is a main determining factor of their effector functions. Hence, the ability of NK cells to withstand and adapt to these metabolically hostile conditions is imperative for effective and sustained antitumor activity in the TME. With this in mind, we review the consequences of metabolic hostility in the TME on NK cell metabolism and function. We also discuss tumor-like metabolic programs in NK cell induced by STAT3-mediated expansion that adapt NK cells to thrive in the TME. Finally, we examine how other approaches can be applied to enhance NK cell metabolism in tumors.
    Keywords:  cancer immunotherapy; immunometabolism; metabolic reprogramming; natural killer cells; tumor metabolism
    DOI:  https://doi.org/10.1111/imr.13316
  3. J Exp Clin Cancer Res. 2024 Mar 08. 43(1): 74
    A glutamine tug-of-war between cancer and immune cells: recent advances in unraveling the ongoing battle.
    Bolin Wang, Jinli Pei, Shengnan Xu, Jie Liu, Jinming Yu.
      Glutamine metabolism plays a pivotal role in cancer progression, immune cell function, and the modulation of the tumor microenvironment. Dysregulated glutamine metabolism has been implicated in cancer development and immune responses, supported by mounting evidence. Cancer cells heavily rely on glutamine as a critical nutrient for survival and proliferation, while immune cells require glutamine for activation and proliferation during immune reactions. This metabolic competition creates a dynamic tug-of-war between cancer and immune cells. Targeting glutamine transporters and downstream enzymes involved in glutamine metabolism holds significant promise in enhancing anti-tumor immunity. A comprehensive understanding of the intricate molecular mechanisms underlying this interplay is crucial for developing innovative therapeutic approaches that improve anti-tumor immunity and patient outcomes. In this review, we provide a comprehensive overview of recent advances in unraveling the tug-of-war of glutamine metabolism between cancer and immune cells and explore potential applications of basic science discoveries in the clinical setting. Further investigations into the regulation of glutamine metabolism in cancer and immune cells are expected to yield valuable insights, paving the way for future therapeutic interventions.
    Keywords:  Cancer; Glutamine metabolism; Immune cells; Therapeutic strategies; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13046-024-02994-0
  4. Innovation (Camb). 2024 Mar 04. 5(2): 100583
    Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth.
    Johan Gustafsson, Fariba Roshanzamir, Anders Hagnestål, Sagar M Patel, Oseeyi I Daudu, Donald F Becker, Jonathan L Robinson, Jens Nielsen.
      The tumor microenvironment is composed of a complex mixture of different cell types interacting under conditions of nutrient deprivation, but the metabolism therein is not fully understood due to difficulties in measuring metabolic fluxes and exchange of metabolites between different cell types in vivo. Genome-scale metabolic modeling enables estimation of such exchange fluxes as well as an opportunity to gain insight into the metabolic behavior of individual cell types. Here, we estimated the availability of nutrients and oxygen within the tumor microenvironment using concentration measurements from blood together with a metabolite diffusion model. In addition, we developed an approach to efficiently apply enzyme usage constraints in a comprehensive metabolic model of human cells. The combined modeling reproduced severe hypoxic conditions and the Warburg effect, and we found that limitations in enzymatic capacity contribute to cancer cells' preferential use of glutamine as a substrate to the citric acid cycle. Furthermore, we investigated the common hypothesis that some stromal cells are exploited by cancer cells to produce metabolites useful for the cancer cells. We identified over 200 potential metabolites that could support collaboration between cancer cells and cancer-associated fibroblasts, but when limiting to metabolites previously identified to participate in such collaboration, no growth advantage was observed. Our work highlights the importance of enzymatic capacity limitations for cell behaviors and exemplifies the utility of enzyme-constrained models for accurate prediction of metabolism in cells and tumor microenvironments.
    DOI:  https://doi.org/10.1016/j.xinn.2024.100583
  5. J Transl Med. 2024 Mar 03. 22(1): 229
    Advances in metabolic reprogramming of NK cells in the tumor microenvironment on the impact of NK therapy.
    Linxuan Miao, Chenglin Lu, Bin Zhang, Huili Li, Xu Zhao, Haoran Chen, Ying Liu, Xiaonan Cui.
      Natural killer (NK) cells are unique from other immune cells in that they can rapidly kill multiple neighboring cells without the need for antigenic pre-sensitization once the cells display surface markers associated with oncogenic transformation. Given the dynamic role of NK cells in tumor surveillance, NK cell-based immunotherapy is rapidly becoming a "new force" in tumor immunotherapy. However, challenges remain in the use of NK cell immunotherapy in the treatment of solid tumors. Many metabolic features of the tumor microenvironment (TME) of solid tumors, including oxygen and nutrient (e.g., glucose, amino acids) deprivation, accumulation of specific metabolites (e.g., lactate, adenosine), and limited availability of signaling molecules that allow for metabolic reorganization, multifactorial shaping of the immune-suppressing TME impairs tumor-infiltrating NK cell function. This becomes a key barrier limiting the success of NK cell immunotherapy in solid tumors. Restoration of endogenous NK cells in the TME or overt transfer of functionally improved NK cells holds great promise in cancer therapy. In this paper, we summarize the metabolic biology of NK cells, discuss the effects of TME on NK cell metabolism and effector functions, and review emerging strategies for targeting metabolism-improved NK cell immunotherapy in the TME to circumvent these barriers to achieve superior efficacy of NK cell immunotherapy.
    Keywords:  Immunotherapy; Natural killer cells; Solid tumors; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12967-024-05033-w
  6. J Cancer. 2024 ;15(7): 2003-2023
    Overcoming the limitations of immunotherapy in pancreatic ductal adenocarcinoma: Combining radiotherapy and metabolic targeting therapy.
    Han Zhang, Wenjin Xu, Haitao Zhu, Xuelian Chen, Hsiang-I Tsai.
      As a novel anticancer therapy, immunotherapy has demonstrated robust efficacy against a few solid tumors but poor efficacy against pancreatic ductal adenocarcinoma (PDAC). This poor outcome is primarily attributable to the intrinsic cancer cell resistance and T-cell exhaustion, which is also the reason for the failure of conventional therapy. The present review summarizes the current PDAC immunotherapy avenues and the underlying resistance mechanisms. Then, the review discusses synergistic combination therapies, such as radiotherapy (RT) and metabolic targeting. Research suggests that RT boosts the antigen of PDAC, which facilitates the anti-tumor immune cell infiltration and exerts function. Metabolic reprogramming contributes to restoring the exhausted T cell function. The current review will help in tailoring combination regimens to enhance the efficacy of immunotherapy. In addition, it will help provide new approaches to address the limitations of the immunosuppressive tumor microenvironment (TME) by examining the relationship among immunotherapy, RT, and metabolism targeting therapy in PDAC.
    Keywords:  immunotherapy; metabolic reprogramming; pancreatic ductal adenocarcinoma; radiotherapy; tumor microenvironment
    DOI:  https://doi.org/10.7150/jca.92502
  7. Trends Endocrinol Metab. 2024 Mar 06. pii: S1043-2760(24)00037-7. [Epub ahead of print]
    Metabolic remodeling in cancer and senescence and its therapeutic implications.
    Yeonju Kim, Yeji Jang, Mi-Sung Kim, Chanhee Kang.
      Cellular metabolism is a flexible and plastic network that often dictates physiological and pathological states of the cell, including differentiation, cancer, and aging. Recent advances in cancer metabolism represent a tremendous opportunity to treat cancer by targeting its altered metabolism. Interestingly, despite their stable growth arrest, senescent cells - a critical component of the aging process - undergo metabolic changes similar to cancer metabolism. A deeper understanding of the similarities and differences between these disparate pathological conditions will help identify which metabolic reprogramming is most relevant to the therapeutic liabilities of senescence. Here, we compare and contrast cancer and senescence metabolism and discuss how metabolic therapies can be established as a new modality of senotherapy for healthy aging.
    Keywords:  aging; cancer; metabolism; senescence; senotherapy
    DOI:  https://doi.org/10.1016/j.tem.2024.02.008
  8. Cell Death Discov. 2024 Mar 07. 10(1): 118
    The effects of metabolism on the immune microenvironment in colorectal cancer.
    Xingzhao Chen, Zhiyuan Ma, Zhiqiang Yi, Enqin Wu, Zhengye Shang, Biguang Tuo, Taolang Li, Xuemei Liu.
      Colorectal cancer (CRC) is a malignancy that is widely prevalent worldwide. Due to its unsatisfactory treatment outcome and extremely poor prognosis, many studies on the molecular mechanisms and pathological mechanisms of CRC have been published in recent years. The tumor microenvironment (TME) is an extremely important feature of tumorigenesis and one of the hallmarks of tumor development. Metabolic reprogramming is currently a hot topic in tumor research, and studies on this topic have provided important insights into CRC development. In particular, metabolic reprogramming in cancer causes changes in the composition of energy and nutrients in the TME. Furthermore, it can alter the complex crosstalk between immune cells and associated immune factors, such as associated macrophages and T cells, which play important immune roles in the TME, in turn affecting the immune escape of tumors by altering immune surveillance. In this review, we summarize several metabolism-related processes affecting the immune microenvironment of CRC tumors. Our results showed that the immune microenvironment is regulated by metabolic reprogramming and influences the development of CRC.
    DOI:  https://doi.org/10.1038/s41420-024-01865-z
  9. Nat Commun. 2024 Mar 05. 15(1): 1987
    Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression.
    Fatima Khan, Yiyun Lin, Heba Ali, Lizhi Pang, Madeline Dunterman, Wen-Hao Hsu, Katie Frenis, R Grant Rowe, Derek A Wainwright, Kathleen McCortney, Leah K Billingham, Jason Miska, Craig Horbinski, Maciej S Lesniak, Peiwen Chen.
      Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling and functional studies demonstrate that lactate dehydrogenase A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer and activator of transcription 3 (STAT3) transcriptional co-activators in glioblastoma cells to upregulate C-C motif chemokine ligand 2 (CCL2) and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.
    DOI:  https://doi.org/10.1038/s41467-024-46193-z
  10. Biochem Pharmacol. 2024 Feb 29. pii: S0006-2952(24)00081-9. [Epub ahead of print]222 116098
    Lactic acid in macrophage polarization: A factor in carcinogenesis and a promising target for cancer therapy.
    Mobarakeh Ajam-Hosseini, Romina Heydari, Milad Rasouli, Fatemeh Akhoondi, Niloofar Asadi Hanjani, Sander Bekeschus, Mohammad Doroudian.
      Cancer remains a formidable challenge, continually revealing its intricate nature and demanding novel treatment approaches. Within this intricate landscape, the tumor microenvironment and its dynamic components have gained prominence, particularly macrophages that can adopt diverse polarization states, exerting a profound influence on cancer progression. Recent revelations have spotlighted lactic acid as a pivotal player in this complex interplay. This review systematically explores lactic acid's multifaceted role in macrophage polarization, focusing on its implications in carcinogenesis. We commence by cultivating a comprehensive understanding of the tumor microenvironment and the pivotal roles played by macrophages. The dynamic landscape of macrophage polarization, typified by M1 and M2 phenotypes, is dissected to reveal its substantial impact on tumor progression. Lactic acid, a metabolic byproduct, emerges as a key protagonist, and we meticulously unravel the mechanisms underpinning its generation within cancer cells, shedding light on its intimate association with glycolysis and its transformative effects on the tumor microenvironment. Furthermore, we decipher the intricate molecular framework that underlies lactic acid's pivotal role in facilitating macrophage polarization. Our review underscores lactic acid's dual role in carcinogenesis, orchestrating tumor growth and immune modulation within the tumor microenvironment, thereby profoundly influencing the balance between pro-tumor and anti-tumor immune responses. This duality highlights the therapeutic potential of selectively manipulating lactic acid metabolism for cancer treatment. Exploring strategies to inhibit lactic acid production by tumor cells, novel approaches to impede lactic acid transport in the tumor microenvironment, and the burgeoning field of immunotherapeutic cancer therapies utilizing lactic acid-induced macrophage polarization form the core of our investigation.
    Keywords:  Blocking strategies; Cancer therapy; Lactic acid; Macrophage polarization; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.bcp.2024.116098
  11. J Clin Invest. 2024 Mar 05. pii: e170071. [Epub ahead of print]
    CD8+ T cells sustain antitumor response by mediating crosstalk between adenosine A2A receptor and glutathione/GPX4.
    Siqi Chen, Jie Fan, Ping Xie, Jihae Ahn, Michelle Fernandez, Leah K Billingham, Jason Miska, Jennifer D Wu, Derek A Wainwright, Deyu Fang, Jeffrey A Sosman, Yong Wan, Yi Zhang, Navdeep S Chandel, Bin Zhang.
      Antitumor responses of CD8+ T cells are tightly regulated by distinct metabolic fitness. High levels of glutathione (GSH) are observed in the majority of tumors contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4 (GPX4) dependent ferroptosis. Here, we show the necessity of the adenosine A2A receptor (A2AR) signaling and the glutathione (GSH)-GPX4 axis in orchestrating metabolic fitness and survival of functionally competent CD8+ T cells. Activated CD8+ T cells treated ex vivo with simultaneous inhibition of A2AR and lipid peroxidation acquire a superior capacity to proliferate and persist in vivo, demonstrating a translatable means to prevent ferroptosis in adoptive cell therapy (ACT). Additionally, we identify a particular cluster of intratumoral CD8+ T cells expressing a putative gene signature of GSH metabolism (GMGS) in association with clinical response and survival across several human cancers. Our study addresses a key role of GSH-GPX4 and adenosinergic pathways in fine-tuning the metabolic fitness of antitumor CD8+ T cells.
    Keywords:  Cancer immunotherapy; Immunology; Metabolism; T cells
    DOI:  https://doi.org/10.1172/JCI170071
  12. Front Mol Biosci. 2024 ;11 1343523
    Dynamic interactions in the tumor niche: how the cross-talk between CAFs and the tumor microenvironment impacts resistance to therapy.
    Oliwia Piwocka, Igor Piotrowski, Wiktoria M Suchorska, Katarzyna Kulcenty.
      The tumor microenvironment (TME) is a complex ecosystem of cells, signaling molecules, and extracellular matrix components that profoundly influence cancer progression. Among the key players in the TME, cancer-associated fibroblasts (CAFs) have gained increasing attention for their diverse and influential roles. CAFs are activated fibroblasts found abundantly within the TME of various cancer types. CAFs contribute significantly to tumor progression by promoting angiogenesis, remodeling the extracellular matrix, and modulating immune cell infiltration. In order to influence the microenvironment, CAFs engage in cross-talk with immune cells, cancer cells, and other stromal components through paracrine signaling and direct cell-cell interactions. This cross-talk can result in immunosuppression, tumor cell proliferation, and epithelial-mesenchymal transition, contributing to disease progression. Emerging evidence suggests that CAFs play a crucial role in therapy resistance, including resistance to chemotherapy and radiotherapy. CAFs can modulate the tumor response to treatment by secreting factors that promote drug efflux, enhance DNA repair mechanisms, and suppress apoptosis pathways. This paper aims to understand the multifaceted functions of CAFs within the TME, discusses cross-talk between CAFs with other TME cells, and sheds light on the contibution of CAFs to therapy resistance. Targeting CAFs or disrupting their cross-talk with other cells holds promise for overcoming drug resistance and improving the treatment efficacy of various cancer types.
    Keywords:  cancer; cancer-associated fibroblasts; cross-talk; radiotherapy; therapy resistance; tumor-microenvironment
    DOI:  https://doi.org/10.3389/fmolb.2024.1343523
  13. Cancer Res Commun. 2024 Mar 07.
    Targeting tryptophan catabolism in ovarian cancer to attenuate macrophage infiltration and PD-L1 expression.
    Lyndsey S Crump, Jessica L Floyd, Li-Wei Kuo, Miriam D Post, Mike Bickerdike, Kathleen O'Neill, Kayla Sompel, Kimberly R Jordan, Bradley R Corr, Nicole Marjon, Elizabeth R Woodruff, Jennifer K Richer, Benjamin G Bitler.
      High grade serous carcinoma (HGSC) of the fallopian tube, ovary and peritoneum is the most common type of ovarian cancer and is predicted to be immunogenic since the presence of tumor-infiltrating lymphocytes conveys a better prognosis. However, the efficacy of immunotherapies has been limited due to the immune-suppressed tumor microenvironment (TME). Tumor metabolism and immune-suppressive metabolites directly affect immune cell function through the depletion of nutrients and activation of immune-suppressive transcriptional programs. Tryptophan (TRP) catabolism is a contributor to HGSC disease progression. Two structurally distinct rate-limiting TRP catabolizing enzymes, Indoleamine 2,3-Dioxygenase 1 (IDO1) and Tryptophan 2,3-Dioxygenase 2 (TDO2), evolved separately to catabolize TRP. IDO1/TDO2 are aberrantly expressed in carcinomas and metabolize TRP into the immune-suppressive metabolite kynurenine (KYN), which can engage the aryl hydrocarbon receptor (AhR) to drive immunosuppressive transcriptional programs. To date, IDO inhibitors tested in clinical trials have had limited efficacy, but those inhibitors did not target TDO2, and we find that HGSC cell lines and clinical outcomes are more dependent on TDO2 than IDO1. To identify inflammatory HGSC cancers with poor prognosis, we stratified patient ascites samples by IL6 status, which correlates with poor prognosis. Metabolomics revealed that IL6 high patient samples had enriched KYN. TDO2 knockdown significantly inhibited HGSC growth and TRP catabolism. The orally available dual IDO1/TDO2 inhibitor, AT-0174, significantly inhibited tumor progression, reduced tumor-associated macrophages, and reduced expression of immune-suppressive proteins on immune and tumor cells. These studies demonstrate the importance of TDO2 and the therapeutic potential of AT-0174 to overcome an immune-suppressed TME.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-23-0513
  14. Front Oncol. 2024 ;14 1286896
    Metabolomics analysis reveals novel serum metabolite alterations in cancer cachexia.
    Tushar H More, Karsten Hiller, Martin Seifert, Thomas Illig, Rudi Schmidt, Raphael Gronauer, Thomas von Hahn, Hauke Weilert, Axel Stang.
       Background: Cachexia is a body wasting syndrome that significantly affects well-being and prognosis of cancer patients, without effective treatment. Serum metabolites take part in pathophysiological processes of cancer cachexia, but apart from altered levels of select serum metabolites, little is known on the global changes of the overall serum metabolome, which represents a functional readout of the whole-body metabolic state. Here, we aimed to comprehensively characterize serum metabolite alterations and analyze associated pathways in cachectic cancer patients to gain new insights that could help instruct strategies for novel interventions of greater clinical benefit.
    Methods: Serum was sampled from 120 metastatic cancer patients (stage UICC IV). Patients were grouped as cachectic or non-cachectic according to the criteria for cancer cachexia agreed upon international consensus (main criterium: weight loss adjusted to body mass index). Samples were pooled by cachexia phenotype and assayed using non-targeted gas chromatography-mass spectrometry (GC-MS). Normalized metabolite levels were compared using t-test (p < 0.05, adjusted for false discovery rate) and partial least squares discriminant analysis (PLS-DA). Machine-learning models were applied to identify metabolite signatures for separating cachexia states. Significant metabolites underwent MetaboAnalyst 5.0 pathway analysis.
    Results: Comparative analyses included 78 cachectic and 42 non-cachectic patients. Cachectic patients exhibited 19 annotable, significantly elevated (including glucose and fructose) or decreased (mostly amino acids) metabolites associating with aminoacyl-tRNA, glutathione and amino acid metabolism pathways. PLS-DA showed distinct clusters (accuracy: 85.6%), and machine-learning models identified metabolic signatures for separating cachectic states (accuracy: 83.2%; area under ROC: 88.0%). We newly identified altered blood levels of erythronic acid and glucuronic acid in human cancer cachexia, potentially linked to pentose-phosphate and detoxification pathways.
    Conclusion: We found both known and yet unknown serum metabolite and metabolic pathway alterations in cachectic cancer patients that collectively support a whole-body metabolic state with impaired detoxification capability, altered glucose and fructose metabolism, and substrate supply for increased and/or distinct metabolic needs of cachexia-associated tumors. These findings together imply vulnerabilities, dependencies and targets for novel interventions that have potential to make a significant impact on future research in an important field of cancer patient care.
    Keywords:  GC-MS metabolomics; body metabolism; cancer cachexia; erythronic acid; glucuronic acid; metabolic pathways; serum metabolites
    DOI:  https://doi.org/10.3389/fonc.2024.1286896
  15. Proc Natl Acad Sci U S A. 2024 Mar 12. 121(11): e2319254121
    Fatty acid oxidation fuels natural killer cell responses against infection and cancer.
    Sam Sheppard, Katja Srpan, Wendy Lin, Mariah Lee, Rebecca B Delconte, Mark Owyong, Peter Carmeliet, Daniel M Davis, Joao B Xavier, Katharine C Hsu, Joseph C Sun.
      Natural killer (NK) cells are a vital part of the innate immune system capable of rapidly clearing mutated or infected cells from the body and promoting an immune response. Here, we find that NK cells activated by viral infection or tumor challenge increase uptake of fatty acids and their expression of carnitine palmitoyltransferase I (CPT1A), a critical enzyme for long-chain fatty acid oxidation. Using a mouse model with an NK cell-specific deletion of CPT1A, combined with stable 13C isotope tracing, we observe reduced mitochondrial function and fatty acid-derived aspartate production in CPT1A-deficient NK cells. Furthermore, CPT1A-deficient NK cells show reduced proliferation after viral infection and diminished protection against cancer due to impaired actin cytoskeleton rearrangement. Together, our findings highlight that fatty acid oxidation promotes NK cell metabolic resilience, processes that can be optimized in NK cell-based immunotherapies.
    Keywords:  NK cells; T cells; cancer; metabolism; virus infection
    DOI:  https://doi.org/10.1073/pnas.2319254121
  16. Nat Biomed Eng. 2024 Mar 04.
    Severely polarized extracellular acidity around tumour cells.
    Qiang Feng, Zachary Bennett, Anthony Grichuk, Raymundo Pantoja, Tongyi Huang, Brandon Faubert, Gang Huang, Mingyi Chen, Ralph J DeBerardinis, Baran D Sumer, Jinming Gao.
      Extracellular pH impacts many molecular, cellular and physiological processes, and hence is tightly regulated. Yet, in tumours, dysregulated cancer cell metabolism and poor vascular perfusion cause the tumour microenvironment to become acidic. Here by leveraging fluorescent pH nanoprobes with a transistor-like activation profile at a pH of 5.3, we show that, in cancer cells, hydronium ions are excreted into a small extracellular region. Such severely polarized acidity (pH <5.3) is primarily caused by the directional co-export of protons and lactate, as we show for a diverse panel of cancer cell types via the genetic knockout or inhibition of monocarboxylate transporters, and also via nanoprobe activation in multiple tumour models in mice. We also observed that such spot acidification in ex vivo stained snap-frozen human squamous cell carcinoma tissue correlated with the expression of monocarboxylate transporters and with the exclusion of cytotoxic T cells. Severely spatially polarized tumour acidity could be leveraged for cancer diagnosis and therapy.
    DOI:  https://doi.org/10.1038/s41551-024-01178-7
  17. Clin Transl Med. 2024 Mar;14(3): e1614
    Histone lactylation bridges metabolic reprogramming and epigenetic rewiring in driving carcinogenesis: Oncometabolite fuels oncogenic transcription.
    Yu Zhang, Hang Song, Meili Li, Peirong Lu.
      Heightened lactate production in cancer cells has been linked to various cellular mechanisms such as angiogenesis, hypoxia, macrophage polarisation and T-cell dysfunction. The lactate-induced lactylation of histone lysine residues is noteworthy, as it functions as an epigenetic modification that directly augments gene transcription from chromatin. This epigenetic modification originating from lactate effectively fosters a reliance on transcription, thereby expediting tumour progression and development. Herein, this review explores the correlation between histone lactylation and cancer characteristics, revealing histone lactylation as an innovative epigenetic process that enhances the vulnerability of cells to malignancy. Moreover, it is imperative to acknowledge the paramount importance of acknowledging innovative therapeutic methodologies for proficiently managing cancer by precisely targeting lactate signalling. This comprehensive review illuminates a crucial yet inadequately investigated aspect of histone lactylation, providing valuable insights into its clinical ramifications and prospective therapeutic interventions centred on lactylation.
    Keywords:  cancer; histone lactylation; metabolic reprogramming
    DOI:  https://doi.org/10.1002/ctm2.1614
  18. Heliyon. 2024 Mar 15. 10(5): e27022
    Identification of the novel biomarkers involved in the mitochondrial metabolism-related reactive oxygen species and their role in lung cancer T-cell exhaustion and immunotherapy.
    Sheng Wang, Bo Liu, Fang Li, Zhe Tang, Xuyu Gu, Xianglin Yuan.
       Purpose: To study the role of mitochondrial metabolism and obtain novel biomarkers in immunotherapy for non-small cell lung cancer (NSCLC).
    Methods: We collected the 188 genes involved in mitochondrial metabolism(MMGs) from the MSIGDB project and then quantified the activity of mitochondrial metabolism. All the NSCLC patients were divided into C1 and C2 clusters based on the 26 prognosis-related MMGs. The differences in biology, differential immune microenvironment, chronic hypoxia and prognosis between C1 and C2 patients were also analyzed. In addition, we validated the results of bioinformatics analysis in lung cancer tissues and cell lines.
    Results: Patients in the C2 cluster had a higher level of mitochondrial metabolism. Patients in the C2 cluster responded better to immunotherapy and had a lower level of T-cell exclusion. The markers of T-cell failure were upregulated in the C1 patients. Hypoxia can lead to a high percentage of C1 patients. ADH1C might be involved in mitochondrial metabolism and immunotherapy response, which can be affected by hypoxia, making it an underlying biomarker. The expression levels of ADH1C in BEAS-2B, H1299, A549 and H460 cells were detected, revealing that ADH1C is upregulated in lung cancer cells. We observed that patients with low ADH1C expression had a longer survival time. The enzyme activities of HK, PK, LDH and SDH were significantly reduced in H1299 and H460 cells with ADH1C knockdown, along with more ROS. Furthermore, the expression levels of PD-L1 and HHLA2 in tumor tissues were analyzed, which found that ADH1C was significantly positively correlated with the expression of PD-L1 and HHLA2.
    Conclusions: In summary, our study comprehensively explored the molecules involved in mitochondrial metabolism and their role in immunotherapy and T lymphocyte failure.
    Keywords:  ADH1C; Immunotherapy; Mitochondrial metabolism; Non-small cell lung cancer; T lymphocyte failure
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e27022
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